Familial frontotemporal lobar degeneration

Abstract Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia, and is characterized by neurodegeneration of the frontal and temporal lobes. The disease typically presents with behavioral disturbances and language difficulties that occur before the age of 65 years. An autosomal dominant familial form of FTLD can be caused by mutations in microtubule-associated protein tau or progranulin, and the chromosome 9 open reading frame 72 repeat expansion. There currently is no therapy available to prevent or cure FTLD. In order to develop a disease-modifying therapy, knowledge concerning the pathophysiological process is crucial to identify proper treatment targets. The familial forms of FTLD can teach us a lot about the disease process by enabling us to explore clinical and pathological characteristics in relation to genetic defects. In this thesis we have expanded knowledge genetic forms of FTLD by reporting clinical and pathological characteristics of a novel GRN mutation and the C9orf72 repeat expansion. Moreover, we have demonstrated that using several MRI techniques, including diffusion tensor imaging, resting-state fMRI, and arterial spin labeling, brain changes can be detected in the presymptomatic stage of FTLD. Therefore, thes

Sharing a Top Manager’s Experience with the Next Generation: The Use of Electronic Discussions and Short Video Fragments in Teaching

In: A.J. Kallenberg and M.J.J.M. van de Ven (Eds), 2002, The New Educational Benefits of ICT in Higher Education: Proceedings. Rotterdam: Erasmus Plus BV, OECR ISBN 90-9016127-9This paper presents an effective educational method to transfer managerial knowledge to students. This method consists among other of online discussions between small groups of students and video clips of lectures. The set-up of the course and the ICT-tool used in the course were evaluated for two years through a questionnaire among the students. The results show that the applied e-learning concept is highly appreciated and serves as an effective tool to exchange knowledge

Altered sense of humor in dementia.

Sense of humor is potentially relevant to social functioning in dementias, but has been little studied in these diseases. We designed a semi-structured informant questionnaire to assess humor behavior and preferences in patients with behavioral variant frontotemporal dementia (bvFTD; n = 15), semantic dementia (SD; n = 7), progressive nonfluent aphasia (PNFA; n = 10), and Alzheimer's disease (AD; n = 16) versus healthy age-matched individuals (n = 21). Altered (including frankly inappropriate) humor responses were significantly more frequent in bvFTD and SD (all patients) than PNFA or AD (around 40% of patients). All patient groups liked satirical and absurdist comedy significantly less than did healthy controls. This pattern was reported premorbidly for satirical comedy in bvFTD, PNFA, and AD. Liking for slapstick comedy did not differ between groups. Altered sense of humor is particularly salient in bvFTD and SD, but also frequent in AD and PNFA. Humor may be a sensitive probe of social cognitive impairment in dementia, with diagnostic, biomarker and social implications

Investigation of the Processability of Polyether Block Amide in High Speed Sintering

The High Speed Sintering (HSS) process ranks among the processes of Powder Bed Fusion of polymers (PBF-P) of Additive Manufacturing (AM). Its scalability, constant layer time and high quality of complex parts compared to other AM processes are some of the characteristics of the HSS showing its potential for series production for small to medium series. Most of the investigations for the PBF-P processes were conducted using commercially available materials like Polyamide 12 (PA12), Polyamide 6 (PA6), Thermoplastic polyurethane (TPU), Polypropylene (PP) and Polybutylene terephthalate (PBT). This work reports from the processing of Polyether block amide (PEBA) in HSS. As a block-copolymer on amide basis, PEBA shows higher performance compared to other block-copolymers like TPU: The high elastic properties, low density and high service temperature make PEBA an ideal material for the use in the athletic footwear and outdoor industry. Until now, no research was conducted on processing PEBA powder in HSS. This work focusses on the material analysis of PEBA powder and manufacturing of specimens of varying sets of process parameters using methods of Design of Experiments (DoE) and IFINAM TPA powder from Evonik. Based on a predictive model, parameter sets for optimum mechanical properties, dimensional accuracy and overall part properties of HSS PEBA parts were optimised within the framework of this work.Mechanical Engineerin

Cortical iron accumulation in MAPT- and C9orf 72-associated frontotemporal lobar degeneration

Neuroinflammation has been implicated in frontotemporal lobar degeneration (FTLD) pathophysiology, including in genetic forms with microtubule-associated protein tau (MAPT) mutations (FTLD-MAPT) or chromosome 9 open reading frame 72 (C9orf72) repeat expansions (FTLD-C9orf72). Iron accumulation as a marker of neuroinflammation has, however, been understudied in genetic FTLD to date. To investigate the occurrence of cortical iron accumulation in FTLD-MAPT and FTLD-C9orf72, iron histopathology was performed on the frontal and temporal cortex of 22 cases (11 FTLD-MAPT and 11 FTLD-C9orf72). We studied patterns of cortical iron accumulation and its colocalization with the corresponding underlying pathologies (tau and TDP-43), brain cells (microglia and astrocytes), and myelination. Further, with ultrahigh field ex vivo MRI on a subset (four FTLD-MAPT and two FTLD-C9orf72), we examined the sensitivity of T2*-weighted MRI for iron in FTLD. Histopathology showed that cortical iron accumulation occurs in both FTLD-MAPT and FTLD-C9orf72 in frontal and temporal cortices, characterized by a diffuse mid-cortical iron-rich band, and by a superficial cortical iron band in some cases. Cortical iron accumulation was associated with the severity of proteinopathy (tau or TDP-43) and neuronal degeneration, in part with clinical severity, and with the presence of activated microglia, reactive astrocytes and myelin loss. Ultra-high field T2*-weighted MRI showed a good correspondence between hypointense changes on MRI and cortical iron observed on histology. We conclude that iron accumulation is a feature of both FTLD-MAPT and FTLD-C9orf72 and is associated with pathological severity. Therefore, in vivo iron imaging using T2*-weighted MRI or quantitative susceptibility mapping may potentially be used as a noninvasive imaging marker to localize pathology in FTLD.</p

Cognitive reserve in granulin-related frontotemporal dementia: from preclinical to clinical stages

OBJECTIVE Consistent with the cognitive reserve hypothesis, higher education and occupation attainments may help persons with neurodegenerative dementias to better withstand neuropathology before developing cognitive impairment. We tested here the cognitive reserve hypothesis in patients with frontotemporal dementia (FTD), with or without pathogenetic granulin mutations (GRN+ and GRN-), and in presymptomatic GRN mutation carriers (aGRN+). METHODS Education and occupation attainments were assessed and combined to define Reserve Index (RI) in 32 FTD patients, i.e. 12 GRN+ and 20 GRN-, and in 17 aGRN+. Changes in functional connectivity were estimated by resting state fMRI, focusing on the salience network (SN), executive network (EN) and bilateral frontoparietal networks (FPNs). Cognitive status was measured by FTD-modified Clinical Dementia Rating Scale. RESULTS In FTD patients higher level of premorbid cognitive reserve was associated with reduced connectivity within the SN and the EN. EN was more involved in FTD patients without GRN mutations, while SN was more affected in GRN pathology. In aGRN+, cognitive reserve was associated with reduced SN. CONCLUSIONS This study suggests that cognitive reserve modulates functional connectivity in patients with FTD, even in monogenic disease. In GRN inherited FTD, cognitive reserve mechanisms operate even in presymptomatic to clinical stages